Project Summary/Abstract Osteogenesis Imperfecta (OI) is a genetic disorder leading to bone deformities, craniofacial abnormalities and fractures, and better pharmacological treatment options are needed. Osteocytes (OT) represent more than 90% of bone cells and regulate bone remodeling. The OT phenotype is altered in OI, suggesting dysregulation of OT function. Intermittent PTH increases bone density and is used for the treatment of osteoporosis, PTHrP is involved in the development of skeletal tissues. Both PTH and PTHrP signal through the same receptor PTH1R. Importantly, PTH1R signaling is required for normal OT function. In a clinical trial, intermittent PTH was ineffective to improve bone density in more severe forms of OI. Because we recently found that TGF? signaling is increased in OI, and TGF? signaling can reduce responsiveness to PTH due to downregulation of PTH1R, we hypothesize that the combined increased TGF? signaling and reduced PTH/PTHrP signaling are a common mechanism of OI contributing to craniofacial defects, bone fragility and OT dysfunction in OI. Hence, in this study we will test to what extent inhibition of TGF? signaling can restore the response to PTH/PTHrP, and hypothesize that combined anti-TGF?/1D11 treatment will synergistically improve the craniofacial abnormities, bone fragility, and OT function in OI. We will test this hypothesis by treating Crtap-/- mice, a model of recessive OI, that recapitulates the human OI phenotype, with a TGF?-inhibitory antibody, intermittent PTH, alone or in combination, or control. After treatment we will determine the effects on the craniofacial phenotype, bone quantity and quality parameters in vertebrae and femurs. Additionally we will determine how the morphology of OT lacunae is altered in OI and how it is affected by anti-TGF?/PTH treatment, and characterize the molecular OT phenotype in OI.